This invention is generally in the area of drug delivery systems and is particularly related to methods of delivery to the lungs and other components of the pulmonary system.
Many drugs are delivered to the lungs where they are designed to have an effect on the tissue of the lungs, for example, vasodilators or surfactants, or within the bronchi, for example, a bronchodilator, or on a tissue within the lung, for example, a chemotherapeutic agent. Other drugs, especially nucleotide drugs, have been delivered to the lungs because it represents a tissue particularly appropriate for treatment, for example, for genetic therapy in cystic fibrosis, where retroviral vectors expressing a defective adenosine deaminase are administered to the lung. Other drugs which have been used with limited success due to difficulties in administration include vaccines, especially for flu and other respiratory illnesses, where the immune cells of the lung are the target.
Advantages of the lungs for delivery of agents having systemic effects include the large amount of surface area and ease of uptake by the mucosal surface.
It is very difficult to deliver drugs into the lungs. Even systemic delivery has limitations, since this requires administration of high dosages in order to achieve an effective concentration within the lungs.
Most drugs now are administered using a dry powder or aerosol inhaler. These devices are limited in efficacy, however, due to problems in trying to get the drugs past all of the natural barriers, such as the cilia lining the trachea, and in trying to administer a uniform volume and weight of powder.
It is therefore an object of the present invention to provide an improved composition for administration of drugs to the pulmonary system.
It is a further object of the present invention to provide a composition for controlled pulsed or sustained administration of the drugs to the pulmonary system.
Drug delivery to the pulmonary system has been achieved by encapsulation of the drug to be delivered in microparticles having a size range between 0.5 and ten microns, preferably in the range of one to five microns, formed of a material releasing drug at a pH of greater than 6.0, preferably between 6.4 and 8.0. In a preferred embodiment, the drug delivery system is based on the formation of diketopiperazine microparticles which are stable at a pH of 6.4 or less and unstable at pH of greater than 6.4, or which are stable at both acidic and basic pH, but which are unstable at pH between about 6.4 and 8. Other types of materials can also be used, including biodegradable natural and synthetic polymers, such as proteins, polymers of mixed amino acids (proteinoids), alginate, and poly(hydroxy acids). In another embodiment, the microparticles have been modified to effect targeting to specific cell types and to effect release only after reaching the targeted cells.
In the most preferred method of manufacture, the microparticles are formed in the presence of the drug to be delivered, for example, proteins or peptides such as insulin or calcitonin, polysaccharides such as heparin, nucleic acid molecules, and synthetic organic pharmaceutical compounds such as felbamate. The diketopiperazine microparticles are preferably formed in the presence of the drug to be encapsulated by: (i) acidification of weakly alkaline solutions of a diketopiperazine derivative that contains one or more acidic groups, (ii) basification of acidic solutions of a diketopiperazine derivative that contains one or more basic groups, or (iii) neutralization of an acidic or basic solution of a zwitterionic diketopiperazine derivative that contains both acidic and basic groups. The size of the resulting microparticles can be controlled by modifying the side-chains on the diketopiperazine, the concentration of various reactants, the conditions used for formation, and the process used in formation. The diketopiperazines can be symmetrically functionalized, wherein the two side-chains are identical, or they can be unsymmetrically functionalized. Both the symmetrically and unsymmetrically functionalized diketopiperazines can have side-chains that contain acidic groups, basic groups, or combinations thereof. Methods that can be used with materials other than the diketopiperazines include spray drying, phase separation, solvent evaporation, and milling, although the latter does not typically yield uniform diameters and can lead to erratic release profiles, which are not desirable. In the preferred embodiment, the microparticles are administered by the use of a dry powderxe2x80x94breath activatedxe2x80x94compressed air inhaler.
Examples demonstrate the administration of calcitonin encapsulated in two micron diameter diketopiperazine microparticles to the pulmonary system of sheep.